Metal-dependent protein phosphatase 1A functions as an extracellular signal-regulated kinase phosphatase.

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  • Additional Information
    • Source:
      Publisher: Published by Blackwell Pub. on behalf of the Federation of European Biochemical Societies Country of Publication: England NLM ID: 101229646 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1742-4658 (Electronic) Linking ISSN: 1742464X NLM ISO Abbreviation: FEBS J Subsets: MEDLINE
    • Publication Information:
      Original Publication: Oxford, UK : Published by Blackwell Pub. on behalf of the Federation of European Biochemical Societies, c2005-
    • Subject Terms:
      Extracellular Signal-Regulated MAP Kinases/*physiology ; Phosphoprotein Phosphatases/*physiology; Amino Acid Sequence ; Amino Acid Substitution/genetics ; Epidermal Growth Factor/metabolism ; Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors ; Extracellular Signal-Regulated MAP Kinases/genetics ; Gene Knockdown Techniques ; HEK293 Cells ; Humans ; Mutagenesis, Site-Directed ; Phosphoprotein Phosphatases/chemistry ; Phosphoprotein Phosphatases/genetics ; Phosphorylation/genetics ; Protein Phosphatase 2C ; Substrate Specificity/genetics
    • Abstract:
      Protein phosphorylation is an important post-translational modification that regulates almost every aspect of signal transduction in cells. Activation of the mitogen-activated protein kinase (MAPK) family kinase extracellular signal-regulated kinase (ERK) is a point of convergence for many cellular activities in response to external stimulation. With stimuli, ERK activity is significantly increased by the phosphorylation of Thr202 and Tyr204 at its activation loop. Downregulation of ERK phosphorylation at these two sites by several phosphatases, such as protein phosphatase 2A, HePTP and MAPK phosphatase 3, is essential for maintaining appropriate ERK function in different cellular processes. However, it is unknown whether metal-dependent protein phosphatase (PPM) family phosphatases directly dephosphorylate ERK. In this study, we found that PPM1A negatively regulated ERK by directly dephosphorylating its pThr202 position early in EGF stimulation. Additional kinetic studies revealed that key residues participated in phospho-ERK recognition by PPM1A. Importantly, PPM1A preferred the phospho-ERK peptide sequence over a panel of other phosphopeptides through the interactions of basic residues in the active site of PPM1A with the pThr-Glu-pTyr motif of ERK. Whereas Lys165 and Arg33 were required for efficient catalysis or phosphosubstrate binding of PPM1A, Gln185 and Arg186 were determinants of PPM1A substrate specificity. The interaction between Arg186 of PPM1A and Glu203 and pTyr204 of phospho-ERK was identified as a hot-spot for phospho-ERK-PPM1A interaction.
      (© 2013 The Authors Journal compilation © 2013 FEBS.)
    • Accession Number:
      62229-50-9 (Epidermal Growth Factor)
      EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
      EC 3.1.3.16 (PPM1A protein, human)
      EC 3.1.3.16 (Phosphoprotein Phosphatases)
      EC 3.1.3.16 (Protein Phosphatase 2C)
    • Publication Date:
      Date Created: 20130409 Date Completed: 20130722 Latest Revision: 20161125
    • Publication Date:
      20231215
    • Accession Number:
      10.1111/febs.12275
    • Accession Number:
      23560844